Febrile illnesses account for approximately 20-25% of hospitalizations in Indonesia and present a major cause of morbidity and mortality. Fever can be attributed to noninfectious causes. However in developing countries a clinical presentation with fever is usually linked to an infectious etiology. Though several studies have been implemented to study specific infectious disease agents such as dengue, diarrhea, or influenza-like illness, large-scale studies to identify causes of febrile illnesses in Indonesia have not been conducted. Further there are a reasonable percentage of patients for whom the cause of the infectious etiology is unknown. To identify the etiology of infectious diseases, microscopic examinations, bacterial and viral cultures, molecular, antigen or antibody assays are needed. Clinicians often make the diagnoses solely on the clinical presentation as laboratory diagnostic capacities are lacking, high costs involved in specialized diagnostic testing, or the inability of a majority of patients to afford testing. This can lead to inappropriate clinical management and inappropriate use of expensive antibiotics, which may contribute to increasing drug resistance.

Several studies have been conducted to evaluate febrile illness in various contexts in Indonesia. These studies have identified pathogens in specimens collected from several acute undifferentiated fever studies. One of the first reports was from Jakarta (Anderson et al.) based on the collection of specimens from hospitalized patients with an unapparent febrile illness in 1971-72. Salmonella and arbovirus infections were the major etiologies identified whereas leptospira, rickettsia, brucella and toxoplasma infections were serologically identified in a few patients. Another study during this decade was conducted in Klaten, Central Java in 1978 (Olson et al.) and identified alphavirus and flavivirus as the etiologies of fever. In 1995, Suharti et al. found that dengue comprised only 49% of total clinically suspected dengue cases in Semarang, Central Java. Other etiologies included rickettsia, hantavirus, leptospira, rubella, chikungunya, and influenza. In 2002-2003, Vollaard et al identified the high prevalence of SalmonelIa typhi and parathyphi infections (9% and 3%, respectively) as confirmed by bacterial culture, in ambulatory and hospitalized febrile patients in Jakarta.

In 2005-2006, Gasem et al. emphasized the importance of considering leptospira and rickettsia infections in patients with acute undifferentiated fever in primary health centers and hospitals in Semarang. During the same period Suwandono et al published findings suggesting that dengue should be monitored carefully, as it contributed 15% of acute febrile illness in patients who visited the primary care facilities in Jakarta. Chikungunya shared similar prevalence, but there was no evidence of endemicity. An observational study from 2000-2008 among adults in Bandung by Alisjahbana et al showed similar etiologies of fever among ambulatory and hospitalized patients. In their study the proportion of cases attributable to the different etiologies were: dengue 12%, influenza 10%, chikungunya 8%, and typhoid 2.4%. Unlike in Jakarta, chikungunya cases in Bandung were found all year round. These studies and a national influenza surveillance also detected novel and/or emerging infectious agents such as zika virus in Klaten, hantavirus in Semarang and Bandung, and influenza H5N1 subtype in many areas.

As the studies were designed to test for specific agents, a large proportion of cases remained unidentified. The most frequent etiologies from these studies were also the important agents found in Thailand, Myanmar, Thailand border and Malaysia (Ellis et al., Leelarasamee et al, Brown et al.).

However, these above mentioned studies though useful were limited in their scope to particular regions or etiologies and did not collect clinical data, outcomes, and etiologies to measure disease burden systematically.

This protocol is designed to provide data that represents the epidemiologic profile of infectious diseases in several large hospitals, by conducting a study to record epidemiological data and identify the etiologies of fever. It will attempt to do so by including hospitals and clinical centers in different parts of the country and collaboration with physicians and researchers across Indonesia.

It is hoped that this will lead to recommendations that will impact clinical care and management of patients which could include changes in the diagnostic testing profile currently available as standard of care (SoC) for patients with febrile illnesses. It will also enable the implementation of an effective clinical research network for the study of infectious diseases in Indonesia.

Primary Objective

    To identify the etiology of acute febrile illness cases and evaluate clinical manifestations and outcomes.

Secondary Objective

    1. To provide clinical data that are essential for improving and/or developing clinical management and health policies.
    2. To enhance research capacity and networking for infectious diseases in Indonesia by improving clinical research site capability in conducting research relevant to public health.
    3. To establish a repository of biological specimens for future study, such as determining the etiology of undiagnosed fever and/or its pathogenicity and its public health importance.

Study Progress and Updates

Enrollment

Enrollment detailsThe enrollment period of this observational cohort study was completed in June 2016. A total of 1,492 subjects (864 adults and 628 pediatrics). Details of enrollment per site can be seen in the chart on the right.

Currently, the Data Management team is conducting the Database Quality Assurance (QA), and the Clinical Research Associate (CRA) team in preparing for Site Close-Out Visit (SCV), which will be held in March 2017.

The writing of the final manuscript has started in parallel with the working of the algorithm and finalization of all the tests.

Bacterial and viral infectious diseases are still the leading cause of death in Southeast Asia, comparable to injuries, cardiovascular diseases and other non-communicable diseases. Sepsis is defined as the body’s response to infectious diseases, including bacterial and viral causes. Sepsis should be considered as a medical emergency just like a heart attack or stroke because there is an interruption in the supply of oxygen and nutrients to the tissues, and emergency treatment is required. The definition of sepsis is broader than febrile illness as patients with severe infectious diseases may not present with fever, and infectious causes may be overlooked by physicians. On the other hand, it is not uncommon for patients who are diagnosed with sepsis on admission to later have a confirmed non-infectious diagnosis.

Recognition of sepsis as a specific syndrome is the most important key for improvements in diagnostic and treatment strategies for infectious diseases. The 1992 statement from ACCP/SCCM (American College of Chest Physicians and the Society of Critical Care Medicine) Conference introduced a definition of “systemic inflammatory response syndrome (SIRS)”. SIRS was considered when patients have more than one of the following clinical findings:

  • Body temperature higher than 38oC or lower than 36oC
  • Heart rate higher than 90/min
  • Hyperventilation evidenced by respiratory rate higher than 20/min or PaCO2 lower than 32 mmHg
  • White blood cell count higher than 12,000 cells/uL or lower than 4,000/uL

The European Society of Intensive Care Medicine (ESICM)/SCCM found a problem that 71% of clinicians and researchers cited no common definition of sepsis. In 2001, the criteria of SIRS were revised so that the updated criteria are useful to both clinicians caring for patients at bedside and to researchers designing observational studies. The revised criteria by SCCM/ESICM/ACCP/ATS/SIS were also to respond the sepsis research agenda to include the “standardization of research protocols”. The improvement was focused on an increase in sensitivity to identify most patients with infection, while minimally sacrifice inevitable specificity. The 2003 statement from SCCM/ESICM/ACCP/ATS/SIS Conference introduced the updated definition of sepsis and SIRS (Scheme 1). The use of this definition has been continuously recommended in 2004, 2008 and 2012 surviving sepsis campaign.

A recent study also confirmed that the 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definitions have higher sensitivity to include patients with clinically or microbiology proven infections compared to the 1992 ACCP/SCCM sepsis definition. Of 827 patients admitted to the ICU within a one year period, Weiss et al found that 16 of 282 patients with clinically or microbiologically proven infections did not meet the 1992 ACCP/SCCM sepsis definition, but all 282 patients with clinically or microbiologically proven infections met the 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition. The 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition also has a higher sensitivity to predict death. Therefore, we aim to use the current 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition for inclusion criteria of sepsis patients (Scheme 1) in this sepsis study.

Scheme1

In addition, the recognition of sepsis cannot replace the diagnosis and management of specific clinical syndromes, such as acute diarrhea or acute encephalitis. However, in those patients, sepsis should be considered as an add-on to the diagnosis, and management of sepsis, in general, should not be overlooked. The recent Fluid Expansion as Supportive Therapy (FEAST) study highlights the need for a much greater understanding of this syndrome, its causes and management strategies in resource-limited settings.

Although infectious diseases are major causes of death in Southeast Asia, the epidemiology of its causes is poorly understood. This is largely because a number of tropical infectious diseases cannot be diagnosed by standard microbiology facilities. For example, most viral infections require specific PCR assays, and rickettsial diseases require an extra blood sample on admission and on convalescent phase for definite diagnosis. Understanding the epidemiology of the causes of sepsis is the corner stone to improve guidelines for diagnosis and management of sepsis specific to the area.

The Management of Severe sepsis in Asia’s Intensive Care units (MOSAIC) conducted a multicenter cohort study involving 16 countries in Asia. In 2009, results of this study were reported and indicated an overall hospital mortality rate from all causes of sepsis to be 44.5%. Similarly, a 2-year epidemiological sepsis study conducted at the Prince Songkla University Hospital in Thailand showed that the hospital and ICU mortality rate of severe sepsis and septic shock was 49.7% and 39.2% respectively and that an estimated 40.5% of the total ICU mortality cases of sepsis were felt to be caused by community-acquired disease. A retrospective review of data from 10 provincial hospitals in Northern Thailand compared to the national death registry between 2004 and 2010 revealed an incidence of community-acquired bacteremia (CAB) increasing from 16.7 to 38.1 per 100,000 people per year. Over that same time period the mortality rate associated with CAB increased from 6.9 to 13.7 per 100,000 people per year. Overall, of those patients admitted to the hospitals with CAB 37.5% died within 30 days of admission. These 3 studies serve to confirm the magnitude of the problem in Southeast Asia and the need to collect more empirical data. A review of the literature also confirms that there are very few population-based studies evaluating the incidence, causes and trends in CAB in low- and middle-income countries, an important omission since such information is required for strategic planning of available healthcare resources, together with disease prevention programs.

Current evidence suggests that a wide range of pathogens is responsible for sepsis and severe sepsis in Southeast Asia. An observational study conducted by Suttinont et al in 845 patients in 2006 showed that major causes of acute undifferentiated fever in Thai agricultural workers are leptospirosis (37%), scrub typhus (20%), influenza (11%), murine typhus (2.8%) or other bacterial infection (1.2%). Leptospirosis has also been reported as the major cause of fever in 13/137 in adults in Indonesia. Acute rickettsial infection was also identified as the cause of fever in 115/427 (27%) adults with negative blood cultures admitted to Mahosot Hospital in Vientiane, Laos, and in 9/137 in adults with acute undifferentiated fever in Semarang, Indonesia. Gram-negative aerobes accounted for 90% of causes of sepsis (67% Salmonella typhi, 10% Escherichia coli, 5% Klebsiella spp. and 3% Salmonella para-typhi B) in adults and children admitted to infectious disease hospitals in southern Vietnam. That study highlighted that over 70% of the Salmonella typhi isolated were multi-drug-resistant. Similarly, Salmonella enterica serotype Typhi predominates as the cause of bacteremia in Cambodia, while Burkholderia pseudomallei is a major cause of bacteremia in Thailand. However, estimates vary on the incidence of community-acquired sepsis caused by Burkholderia pseudomallei. A study in Southern Thailand of community-acquired severe sepsis caused by Burkholderia pseudomallei indicated a 3.8% incidence. A recent retrospective review of CAB cases in Northern Thailand between 2004 and 2010 indicated that Burkholderia pseudomallei was the sepsis causative agent in 20.2% of adults, 14.3% of children aged 1-15 years and 1.6% in infants less than one year of age.

In an 8-year-long review of blood culture isolates from patients presenting to the Emergency Department of the Hospital Universiti Sains Malaysia beginning from 2002, 55.2% were found to be caused by gram-negative aerobes. Of these, increased drug resistance was noted with less than 80% sensitivity to ampicillin, cotrimoxazole and ciprofloxacin. Other studies highlight that often the cause of sepsis is unknown and a retrospective review of community-acquired bacteremia studies between 1990 and 2010 in South and South-east Asia identified that pathogenic organisms were only isolated in 12% of adults and 7% of children. The paper argues that better detection would lead to better patient outcomes and improved patient management. Goal-directed therapy and appropriate administration of antibiotics within 6 hours was noted to improve outcomes in sepsis patients at Siriraj Hospital in Bangkok, Thailand.

The first aim of this proposal, therefore, is to determine the causes of severe acute infectious illnesses (presenting with sepsis and requiring hospitalization by attending physicians) at multiple study sites across Southeast Asia. This study will also establish a regional repository of samples with robust clinical data to facilitate future pathogen discovery programs and allow future development and assessment of novel diagnostic tests. As stated above, the causes and incidence of community-acquired sepsis and severe sepsis vary. Treatment is initiated based on a presumptive diagnosis taking into account the clinical presentation, initial laboratory data as well as the local guidelines for the management of sepsis and severe sepsis. In many cases a definitive confirmation of the causative agent is not known until much later if at all. While guidelines are available that provide guidance for the treatment of the common causes of sepsis, some causes require a different choice of antibiotics and anti-viral agents. For example:

  • Burkholderia pseudomallei is intrinsically resistant to commonly used first-line antibiotics which are used to treat sepsis in Southeast Asia including penicillin, aminoglycosides and most cephalosporins. Regimens including ceftazidime or a beta-lactam antibiotic such as one of the carbapenems are also indicated.
  • Listeria monocytogenes possesses a natural in-vitro resistance to older quinolones, fosfomycin, and expanded-spectrum cephalosporins. Treatment is typically based on a synergistic association of high doses of aminopenicillin (ampicillin or amoxicillin) and gentamicin. Although rifampin, vancomycin, linezolid, and carbapenems have been proposed as possible alternatives, trimethoprim is generally used in case of intolerance to beta-lactams.
  • Sepsis caused by the Rickettsiae group of organisms is best treated by early initiation of specific antibiotics including doxycycline, chloramphenicol or a fluoroquinolone.
  • Sepsis and encephalitis caused by Herpes simplex would warrant treatment with intravenous acyclovir.

When considering the prevalence of the different causes of sepsis that this study is likely to encounter at the study sites it is important to consider a sample size that will detect those causes that would lead to a different choice of antibiotics or anti-virals compared to standard therapy. An informal review of hospital records in Ho Chi Minh City in 2012 revealed that the prevalence of Listeria monocytogenes, Burkholderia pseudomallei, Herpes simplex and Rickettsiae organisms as the confirmed cause of community-acquired sepsis and severe sepsis was greater than 2% but less than 5%. Similarly, the recent retrospective study of CAB in Northern Thailand showed that if a 5% prevalence of the difference causes of disease was assumed then this would miss important causes including Burkholderia pseudomallei and Haemophilus influenzae in infants under one year of age (2% and 2.8% prevalence respectively), Streptococcus pneumonia in adults (2.5% prevalence), Group A Streptococcus in all age groups (2.2-3%), and extended spectrum beta lactamase (ESBL) Escherichia coli in adults (2.9% prevalence). These data suggest that a study powered to detect 5% prevalence of any particular cause would likely miss some important causes resulting in cause-appropriate treatment not being administered. This has obvious implications for patient survival, particularly when mortality rates are known to be high if appropriate treatment is not administered quickly. These data would also indicate that detecting a 2% prevalence of the different causes of sepsis would be more clinically appropriate and likely lead to higher survival rates for patients in this study.

Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Around 20-40% of sepsis patients presenting to the hospitals develop severe sepsis, which is associated with a very high mortality rate. Apart from antibiotic and anti-viral treatment being an important component of sepsis survival, the overall comprehensive clinical management of the patient is critical, particularly for those who develop severe sepsis. In 2004, an international group of experts in the diagnosis and management of infectious diseases published the first internationally accepted guidelines that the bedside clinician could use to improve outcomes in severe sepsis (sepsis plus any acute organ dysfunction). This “surviving sepsis campaign (updated in 2008)” aims to increase awareness and improve the acute management in severe sepsis. Acute management of severe sepsis during the first 48 hours is very important to reduce mortality. The MOSAIC’s multinational cohort study reported that the overall compliance with the Surviving Sepsis Campaign’s resuscitation and management bundles for severe sepsis in adult patients in Asian countries was only 7.6% and 3.5% respectively. These numbers are much lower than those reported by other similar studies in Europe and the Americas.

Nonetheless, most of the interventions in the “surviving sepsis campaign” are based on facilities available in the developed world. It is very likely that management of sepsis and severe sepsis varies widely across Southeast Asia, in part due to limited resources.

The second aim of this proposal, therefore, is to observe current acute management (within the first 48 hours) of patients presenting with sepsis and severe sepsis to design practical interventions that could reduce the mortality in the future. This study will observe the routine practice in detection of severe sepsis among sepsis patients, and the overall management of patients with sepsis and severe sepsis at multiple study sites across Southeast Asia. This study will focus on observations of early and basic management, including fluid management, blood pressure control, timely administration of antibiotics, and source control, which is likely to be the most cost-effective intervention even in resource-constrained settings.

Outcome from patients presenting with sepsis and severe sepsis is dependent on many factors, including causes of infection, severity of infection, sepsis resuscitation, antimicrobial treatment and host genetic factors. There is a lack of studies showing genetic factors associated with outcomes in patients with sepsis and severe sepsis in developing countries. A recent retrospective study in 669 Thai patients with culture-proven melioidosis admitted to Sappasithiprasong Hospital shows that hypofunctional genetic variant TLR51174C>T is associated with reduced organ failure and improved survival in melioidosis. Understanding all predictive factors associated with inflammatory responses, organ failure, and mortality of patients with sepsis and severe sepsis, including genetic factors, would be very important to improve the management and outcome of this group of patients in the future. Therefore in this study we will ask adult subjects if they wish to provide one additional sample of blood to be stored for later genetic testing. This is optional and subjects can chose to not consent to providing this additional sample without affecting their eligibility to be part of the sepsis study.

Primary Objective

    To determine the causes of community-acquired sepsis and severe sepsis in adults and pediatrics across Southeast Asia.

Secondary Objective

    1. To define the current acute management (within the first 48 hours after admission) of subjects presenting with community-acquired sepsis and severe sepsis and gaps of current practice as defined by the surviving sepsis campaign 2012. This will provide the basis for designing practical interventions to reduce the mortality of subjects with community-acquired sepsis and severe sepsis in the future.
    2. To define the clinical outcome of community-acquired sepsis and severe sepsis in Southeast Asia.
    3. To identify risk factors associated with sepsis or severe sepsis.
    4. To determine the extent of antimicrobial resistance in organisms that cause community-acquired sepsis and severe sepsis in Southeast Asia and to determine the association between antimicrobial resistance and mortality.
    5. To evaluate the accuracy of selected rapid diagnostic tests (RDTs) in determining the causes of community-acquired sepsis and severe sepsis compared to well-defined gold standard tests.

Study Progress and Updates

The Site Close Out (SCO) visits to all sites were conducted in the 2nd and 3rd week of January 2016. Study team members still need to answer queries, send specimens, complete documents, and many other things for this study. All data will be closed for analysis at the end of March. Specimen testing will start at INA-RESPOND assigned reference laboratories. The results are expected to be valuable for the manuscript writing.

Subject enrollment per 31 December 2015 is as follows:

Screen Shot 2016-02-26 at 15.31.32

Tuberculosis (TB) continues to be a health problem in the world, especially in developing countries and despite the use of anti-TB treatments and BCG vaccination TB incidence continues to rise and is a re-emerging disease that was declared a global health emergency by the World Health Organization (WHO) in 1995. In 2008, WHO estimated that there were 9.2 million new TB patients and 4.1 million of whom were patients with Acid-Fast Bacillus (AFB) positive with a mortality rate of 1.7 million patients per year throughout the world.

Based on the WHO Report 2013, Indonesia ranked third in the world with an estimated prevalence in 2012 is 730,000 cases and TB incidence is 460,000 cases with mortality number 67,000.3 This condition is exacerbated by the increasing incidence of TB/HIV comorbidity and the growing number of cases with TB Multidrug Resistance TB (MDR) or even Extensively or Extremely Drug Resistance (XDR). This situation will lead to an epidemic of TB that is difficult to manage and continues to be a major public health problem. Previous drug resistance TB surveys around Indonesia revealed that in Timika district at Papua 2004, 2% of new TB cases are MDR TB cases, in Central Java province 2006, 1.8% of new TB cases and 17.1% of retreatment TB cases are MDR TB cases. Survey in Makassar 2007 revealed higher number that 4.1% of new TB cases and 19.2% of retreatment TB cases are MDR TB cases. WHO Report 2013 estimation in 2012 for Indonesia gave a lower number which are 1.9% of new TB cases and 12% of retreatment TB cases are MDR TB cases.

The Indonesia Health Profile study reported 194,000 new TB cases in 2011 based on positive smear results. TB control efforts were implemented in Indonesia starting in 1969, Directly Observed Treatment Shortcourse chemotherapy (DOTS) began in 1995. Nevertheless these efforts to date have not eliminated the TB burden.

Treatment success is known to be associated with several factors. These include patient related factors, such as host response, age, gender,smoking habit,nutritional status, comorbidities (diabetes and HIV). Mtb characteristics are also associated with outcome, including number of bacteria and Mtb strain (e.g Beijing strain). Pharmacokinetics and pharmacogenomics, particularly with infections with drug-resistant strains are additionally associated with outcome.

Data on the prevalence of MDR-TB or XDR-TB among naïve or retreatment TB cases is limited to several centers in Indonesia.  This study will be the first to follow up new and previously treated TB patients in hospitals in Indonesia. Prevalence data for drug-susceptible and MDR TB, along with corresponding treatment outcomes, will be beneficial to inform national TB programs.  Additionally, data collected from this study will be useful for planning future research studies in Indonesia  evaluating novel diagnostics, markers of response to treatment and new therapies.

Primary Objective

    To estimate the proportion of MDR TB amongst treatment naïve new treatment naïve and previously treated cases

Secondary Objective

    1. To estimate the proportion of patients cured, lost-to-treatment follow-up, failed and dead amongst treated new and previously  DS-TB cases and amongst MDR-TB cases (WHO 2013)
    2.  To evaluate the association of the following factors with successful  treatment outcomes

Study Progress and Updates

Screening & Enrollment

Like other studies, our TRIPOD study has enrollment targets, and sites are encouraged to meet this target. However, the first year of a study can be quite challenging as there are some un-calculated factors that may affect the ability of sites to meet the study’s enrollment target. This is also true for TRIPOD. By the end of June, 47 patients had been enrolled out of the 309 pre-screened patients. From the chart on the right, we can see that sites’ enrollment number is still below the number of weekly target and need to catch up with the target. Despite of the results, the recruitment activities have been a great lesson for us, and we are sure that we can do better in future.By the end of June 2017, site teams had enrolled 47 subjects. Site 570 – RSUD dr Soetomo, Surabaya is currently the top recruiter with 13 subjects. Enrollment progress up to 2 July 2017 can be seen in the graphic below.

Capture

Interim Analysis Meeting

It has been 6 months since the first TRIPOD site, RS Sanglah, Denpasar was activated in February 2017. We have had several interesting findings and issues related to the study and decided it is a good time to hold an interim analysis meeting to give opportunities for site team members to share their findings and experiences, so we can make some decisions to improve our performance and the quality of our TRIPOD study. Interim analysis meeting will be held on 21 – 22 July 2017. Protocol PI, Site PIs/Co-PIs, and Research Assistants from all active sites are invited in the meeting. We are all looking forward to this meeting.

INA-RESPOND Secretariat